Obesity and type 2 diabetes mellitus (T2DM) are worldwide epidemics and the mechanisms that lead from obesity to abnormal glucose homeostasis remain elusive. Accumulating evidence suggests that the neurons within the hypothalamus that sense peripheral nutrients and hormones to regulate food intake also regulate glucose homeostasis. This raises the possibility that CNS mechanisms could link obesity and T2DM. Glucagon-like peptide-1 (GLP-1), secreted by the intestine, is a potent stimulus for insulin secretion and is essential for normal glucose homeostasis. Several long-acting GLP-1 analogs have recently been developed for the treatment of T2DM. These new GLP-1 based drugs are presumed to work directly on the pancreatic beta- cell to promote insulin release. However, GLP-1 is also made in the brain, with receptors in several key regions implicated in the control of food intake and glucose homeostasis. Our preliminary data indicate that GLP-1 signaling within the hypothalamus regulates peripheral glucose levels and that the ability of CNS GLP-1 to regulate both glucose levels and food intake is dependent on glucose availability. In the beta-cell, the ability of GLP-1 to induce insulin secretion is dependent on elevated ambient glucose concentrations, a key control for homeostatic regulation. Glucokinase (GK) has been proposed to function as a glucose sensor, and we propose that the ability of central GLP-1 to regulate energy and glucose homeostasis is dependent upon glucose availability and that this in turn is regulated via GK. Specifically, the goals of this proposal are to determine which populations of GLP-1r within the CNS are linked to GK function and glucose sensing in regulation of both food intake and glucose homeostasis. The long term goals of this proposal are to elucidate specific cellular and neuronal mechanisms that link obesity to type 2 diabetes mellitus.